[Show abstract][Hide abstract]ABSTRACT:
To study the effectiveness and clinical relevance of eyes treated with good (better than 6/12 or >70 Early Treatment Diabetic Retinopathy Study letters) visual acuity (VA) when initiating treatment with ranibizumab for neovascular age-related macular degeneration (nAMD) in the UK National Health Service. Currently eyes with VA better than (>) 6/12 are not routinely funded for therapy.
Multicentre national nAMD database study on patients treated 3-5 years prior to the analysis. Anonymised structured data were collected from 14 centres. The primary outcome was the mean VA at year 1, 2 and 3. Secondary measures included the number of clinic visits and injections.
The study included 12 951 treatment-naive eyes of 11 135 patients receiving 92 976 ranibizumab treatment episodes. A total of 754 patients had baseline VA better than 6/12 and at least 1-year of follow up. Mean VA of first treated eyes with baseline VA>6/12 at year 1, 2, 3 were 6/10, 6/12, 6/15, respectively and those with baseline VA 6/12 to >6/24 were 6/15, 6/17, 6/20, respectively (p values <0.001 for comparing differences between 6/12 and 6/12-6/24 groups). For the second eyes with baseline VA>6/12, mean VA at year 1, 2, 3 were 6/9, 6/9, 6/10 and those with baseline VA 6/12 to >6/24 were 6/15, 6/15, 6/27, respectively (p values <0.001-0.005). There was no significant difference in the average number of clinic visits or injections between those with VA better and worse than 6/12.
All eyes with baseline VA>6/12 maintained better mean VA than the eyes with baseline VA 6/12 to >6/24 at all time points for at least 2 years. The significantly better visual outcome in patients who were treated with good baseline VA has implications on future policy regarding the treatment criteria for nAMD patients' funding.
Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

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A large number of genes can cause inherited retinal degenerations when mutated. It is important to identify the cause of disease for a better disease prognosis and a possible gene-specific therapeutic intervention.
To identify the cause of disease in families with nonsyndromic retinitis pigmentosa.
Patients and family members were recruited for the study and underwent clinical evaluation and genetic analyses.
Identification of sequence variants in genes using next-generation sequencing.
We performed exome sequencing for 4 families, which was followed by Sanger sequencing of the identified mutations in 120 ethnicity-matched patients. In total, we identified 4 BBS2 missense mutations that cause nonsyndromic retinitis pigmentosa. Three siblings of Moroccan Jewish ancestry were compound heterozygotes for p.A33D and p.P134R, and 6 patients belonging to 4 families of Ashkenazi Jewish ancestry were homozygous for either p.D104A or p.R632P, or compound heterozygous for these 2 mutations. The mutations cosegregated with retinitis pigmentosa in the studied families, and the affected amino acid residues are evolutionarily conserved.
Our study shows that BBS2 mutations can cause nonsyndromic retinitis pigmentosa and highlights yet another candidate for this genetically heterogeneous condition.

[Show abstract][Hide abstract]ABSTRACT:
Purpose
To study the characteristics of second treated eyes in patients with neovascular age-related macular degeneration (nAMD) treated with ranibizumab in the United Kingdom National Health Service.
Design
Multicenter national nAMD database study.
Participants
Twelve thousand nine hundred fifty-one treatment-naïve eyes of 11 135 patients receiving 92 976 ranibizumab injections.
Methods
Up to 5 years of routinely collected, anonymized data within electronic medical record systems were extracted remotely from 14 centers. Participating centers exclusively used ranibizumab to treat nAMD (loading phase of 3 monthly injections followed by monthly visits and pro re nata re-treatment). The minimum data set included: age, logarithm of the minimum angle of resolution (logMAR) visual acuity (VA) at baseline and at all subsequent visits, and injection episodes.
Main Outcome Measures
Baseline, change and actual VA over 3 years, and number of treatments and clinic visits.
Results
During the study, 1816 (16.3%) of the 11 135 patients received treatment to the fellow eye. Mean baseline and final VA were 0.66 (standard deviation, 0.32) and 0.65 (0.40) for first treated eyes and 0.41 (0.34) and 0.56 (0.40) for second treated eyes. The rate of VA loss after the loading phase was similar in first and second treated eyes (0.03 and 0.05 logMAR units/year). When fellow eyes with baseline VA worse than 20/200 were excluded to restrict analyses to eyes at risk of nAMD, the rate of second-eye involvement was 14.0% per year (42%/3 years). Mean number of injections/visits in years 1, 2, and 3 were similar for first and second treated eyes (5.6/8.2, 3.9/8.0, 3.8/8.2 and 5.5/8.7, 3.6/9.4, and 3.8/9.1, respectively).
Conclusions
Second treated eyes with nAMD commence treatment with better baseline VA, do not show significant vision gain but maintain better VA than first treated eyes at all time points for at least 3 years, making them the more important eye functionally. These data highlight the high burden of second eye involvement, with almost half of all eyes at risk requiring bilateral treatment by 3 years, and the need for regular monitoring of fellow eyes for best visual outcomes which theoretically may reduce the benefits of extended monitoring regimens.

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Retinal dystrophies are genetically heterogeneous, resulting from mutations in over 200 genes. Prior to the development of massively parallel sequencing, comprehensive genetic screening was unobtainable for most patients. Identifying the causative genetic mutation facilitates genetic counselling, carrier testing and prenatal/pre-implantation diagnosis, and often leads to a clearer prognosis. In addition, in a proportion of cases, when the mutation is known treatment can be optimised and patients are eligible for enrolment into clinical trials for gene-specific therapies.

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This paper investigates the willingness of adults with inherited retinal disease to undergo and pay for diagnostic genetic testing in three hypothetical scenarios and to explore the factors that influence decision making. Fifty patients were presented with three scenarios whereby genetic testing provided increasing information: confirming the diagnosis and inheritance pattern alone, providing additional information on future visual function, and identifying in addition a new treatment which could stabilise their condition. Willingness to pay (WTP) was elicited using an iterative bidding game. Regression analysis was used to investigate the probability of agreeing to and paying for testing. Qualitative data were also reviewed to provide a comprehensive understanding of WTP and decision making. The majority of participants agreed to undergo genetic testing in each of the three scenarios. Scenario 2 was the least acceptable with 78% of participants agreeing to genetic testing. The probability of agreeing to genetic testing decreased with age. Between 72 and 96% of participants reported a WTP for genetic testing. Average WTP was £539, £1516, and £6895 for scenarios 1, 2, and 3 respectively. Older participants and participants with higher incomes were willing to pay more for testing. Qualitative data provided additional detail about the rationale behind participants' decisions. The study suggests that patients with inherited retinal disease were willing to undergo and to pay for diagnostic genetic testing, suggesting that they valued the information it may provide. However, several patients preferred not to receive prognostic information and were less willing to pay for genetic testing that yielded such detail.European Journal of Human Genetics advance online publication, 11 June 2014; doi:10.1038/ejhg.2014.111.

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Advances in sequencing technology and the movement of genetic testing into all areas of medicine will increase opportunities for molecular confirmation of a clinical diagnosis. For health-care professionals without formal genetics training, there is a need to know what patients understand about genetics and genetic testing and their information needs and preferences for the disclosure of genetic testing results. These topics were explored during face-to-face interviews with 50 adults with inherited retinal disease, selected in order to provide a diversity of opinions. Participants had variable understanding of genetics and genetic testing, including basic concepts such as inheritance patterns and the risk to dependents, and many did not understand the term 'genetic counselling'. Most were keen for extra information on the risk to others, the process for genetic testing and how to share the information with other family members. Participants were divided as to whether genetic testing should be offered at the time of the initial diagnosis or later. Many would prefer the results to be given by face-to-face consultation, supplemented by further information in a format accessible to those with visual impairment. Health-care professionals and either leaflets or websites of trusted agencies were the preferred sources of information. Permission should be sought for disclosure of genetic information to other family members. The information needs of many patients with inherited retinal disease appear to be unmet. An understanding of their information needs and preferences is required to help health-care professionals provide optimal services that meet patient expectations.European Journal of Human Genetics advance online publication, 8 January 2014; doi:10.1038/ejhg.2013.296.

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Availability and accuracy of genetic testing in ophthalmology has increased yet the benefits are unclear especially for those conditions where cure or treatments are limited. To explore attitudes to and patients' understanding of possible advantages and disadvantages of genetic testing for inherited retinal disease, we undertook focus groups in three West Yorkshire towns in the UK. Most of our participants had retinitis pigmentosa and one of the focus groups consisted of participants from (British) Asian ethnic background. Here, we report only those attitudes which were common in all three focus groups. Some of the attitudes have already been reported in the literature. Novel findings include attitudes held towards informed choice and life planning, particularly among more severely affected participants. For example, participants appreciated that genetic testing increases informed choice and enables life planning, but these understandings tended to be in a specific sense: informed choice whether to have children and family planning in order to prevent illness recurrence. We conclude that even though these patients are not a homogeneous group, their attitudes tend to be underpinned by deep anxiety of passing their visual impairment onto their children. In this respect, they differ importantly from a small minority of the deaf who would prefer to have children with hearing loss, and from the more general population who do not believe that blindness is a "severe" enough disability to warrant avoiding having children.

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The views of people with inherited retinal disease are important to help develop health policy and plan services. This study aimed to record levels of understanding of and attitudes to genetic testing for inherited retinal disease, and views on the availability of testing.
Telephone questionnaires comprising quantitative and qualitative items were completed with adults with inherited retinal disease. Participants were recruited via postal invitation (response rate 48%), approach at clinic or newsletters of relevant charitable organisations.
Questionnaires were completed with 200 participants. Responses indicated that participants' perceived understanding of genetic testing for inherited retinal disease was variable. The majority (90%) considered testing to be good/very good and would be likely to undergo genetic testing (90%) if offered. Most supported the provision of diagnostic (97%) and predictive (92%) testing, but support was less strong for testing as part of reproductive planning. Most (87%) agreed with the statement that testing should be offered only after the individual has received genetic counselling from a professional. Subgroup analyses revealed differences associated with participant age, gender, education level and ethnicity (p<0.02). Participants reported a range of perceived benefits (eg, family planning, access to treatment) and risks (eg, impact upon family relationships, emotional consequences).
Adults with inherited retinal disease strongly support the provision of publicly funded genetic testing. Support was stronger for diagnostic and predictive testing than for testing as part of reproductive planning.

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OBJECTIVE: To investigate qualitative and quantitative differences in the structure of the posterior segment of the eye in 1-day post-hatch and 12-month-old retinal dysplasia and degeneration (rdd) and wild-type chickens. ANIMAL STUDIED: Retinal dysplasia and degeneration and wild-type chickens. PROCEDURE: Using a commercially available spectral domain optical coherence tomography (OCT) system, 15° horizontal line scans were performed in both eyes of 24 live birds. Qualitative differences in retinal lamination and choroidal structure were investigated, and retinal and choroidal thickness were measured. RESULTS: Progressive retinal thinning with loss of outer retinal lamination and changes in the appearance of the choroid were seen in the rdd birds. Mean total retinal thickness was 202 μm (SD 7.8) and 251 μm (SD 8.8) in the rdd and wild-type chicks and 154 μm (SD 18) and 280 μm (SD 10.8) in the adult birds. Much of the difference was the result of loss of outer retinal lamination and thickness in the rdd birds. Mean choroidal thickness was 76 μm (SD 19.6) and 112 μm (SD 36.9) in the rdd and wild-type chicks and 85 μm (SD 23.7) and 228 μm (SD 44.1) in the rdd and wild-type adult birds, respectively. CONCLUSIONS: Differences in retinal and choroidal structure and thickness between rdd and wild-type birds were evident on spectral domain OCT imaging at 1-day post-hatch and more marked at 1 year. Spectral domain OCT may provide a reliable end point for therapeutic intervention in this animal model of inherited retinal degeneration.

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AimsTo evaluate the efficacy and safety of intravitreal ranibizumab in patients with choroidal neovascularisation secondary to pathological myopia (myopic CNV). Data are from a pre-planned, 6-month interim analysis.Methods
Phase II, open-label, single arm, multicentre, 12-month study, recruiting patients (aged ≥18 years) with active primary or recurrent subfoveal or juxtafoveal myopic CNV, with a best-corrected visual acuity (BCVA) score of 24-78 Early Treatment Diabetic Retinopathy Study (ETDRS) letters in the study eye and a diagnosis of high myopia of at least -6 dioptres.Patients received 0.5 mg ranibizumab administered intravitreally to the study eye, followed by monthly injections given as needed (based on a predefined algorithm) for up to 11 months.ResultsAt 6 months, mean BCVA improved from baseline by 12.2 letters, as did central macular thickness (in this interim analysis defined as a measure of either central subfield macular thickness or centre point macular thickness) from baseline by 108 μm in the 48 study eyes of 48 patients. Fewer patients had centre-involving intraretinal oedema (13.0% vs 91.5%), intraretinal cysts (10.9% vs 57.4%), or subretinal fluid (13.0% vs 66.0%) at 6 months than at baseline. Patients received a mean of 1.9 retreatments, were satisfied with ranibizumab treatment, and well being was maintained. No new safety signals were identified.Conclusions
Results from the planned interim analysis support the role of ranibizumab in the treatment of myopic CNV, with excellent efficacy achieved with a low number of injections and few serious adverse events.Eye advance online publication, 1 March 2013; doi:10.1038/eye.2013.8.

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Whilst the majority of inherited diseases have been found to be caused by single base substitutions, small insertions or deletions (<1Kb), a significant proportion of genetic variability is due to copy number variation (CNV). The possible role of CNV in monogenic and complex diseases has recently attracted considerable interest. However, until the development of whole genome, oligonucleotide micro-arrays, designed specifically to detect the presence of copy number variation, it was not easy to screen an individual for the presence of unknown deletions or duplications with sizes below the level of sensitivity of optical microscopy (3-5 Mb). Now that currently available oligonucleotide micro-arrays have in excess of a million probes, the problem of copy number analysis has moved from one of data production to that of data analysis. We have developed CNViewer, to identify copy number variation that co-segregates with a disease phenotype in small nuclear families, from genome-wide oligonucleotide micro-array data. This freely available program should constitute a useful addition to the diagnostic armamentarium of clinical geneticists.

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Leber congenital amaurosis (LCA) is a blinding retinal disease that presents within the first year after birth. Using exome sequencing, we identified mutations in the nicotinamide adenine dinucleotide (NAD) synthase gene NMNAT1 encoding nicotinamide mononucleotide adenylyltransferase 1 in eight families with LCA, including the family in which LCA was originally linked to the LCA9 locus. Notably, all individuals with NMNAT1 mutations also have macular colobomas, which are severe degenerative entities of the central retina (fovea) devoid of tissue and photoreceptors. Functional assays of the proteins encoded by the mutant alleles identified in our study showed that the mutations reduce the enzymatic activity of NMNAT1 in NAD biosynthesis and affect protein folding. Of note, recent characterization of the slow Wallerian degeneration (Wld(s)) mouse model, in which prolonged axonal survival after injury is observed, identified NMNAT1 as a neuroprotective protein when ectopically expressed. Our findings identify a new disease mechanism underlying LCA and provide the first link between endogenous NMNAT1 dysfunction and a human nervous system disorder.

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The aim of this study was to evaluate trends in visual impairment certification due to age-related macular degeneration (ARMD) in the Leeds metropolitan area between 2005 and 2010.
In this retrospective study, the primary causes of visual impairment certification in the Leeds metropolitan area between 2005 and 2010 were reviewed. ARMD was considered to be the cause of certification when recorded as the primary factor contributing to visual impairment in one or both eyes. The incidence of visual impairment certification due to ARMD was calculated using population estimates from the Office of National Statistics.
ARMD was the primary cause of visual impairment certification in all study years, accounting for 58.7 and 50.8% of certifications in 2005 and 2010, respectively. For the same period, the incidence of certification due to ARMD fell from 364 to 248 per million population per year. This was largely the result of a fall in the incidence of visual impairment certification due to neovascular ARMD from 225 to 137 per million population per year, beginning in 2008 after the introduction of a local commissioning policy on the use of intra-vitreal ranibizumab.
The incidence of visual impairment certification due to ARMD in the Leeds metropolitan area appears to be falling. This is largely the result of a decrease in certification secondary to neovascular ARMD. This represents a change in the previously described trend for ARMD visual impairment certification.

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This study reports the incidence of visual impairment certification due to diabetic retinopathy in Leeds between 2008 and 2010 and makes a comparison with data from 2005, immediately before the introduction of a comprehensive screening service.
The primary causes of visual impairment certification between 2008 and 2010 were collected and reviewed. Mid-year population estimates and a diabetes prevalence model were used to determine the incidence of certification secondary to diabetic retinopathy.
Diabetic retinopathy was the primary cause of visual impairment certification in 33 of 446 (7.4%) certificates in 2008, 34 of 410 (8.3%) certificates in 2009 and 24 of 392 (6.1%) in 2010. For the total population in 2008, 2009 and 2010, the combined incidence of either sight impairment or severe sight impairment due to diabetic retinopathy was 42.3, 43.2 and 30 per million per year, respectively. For the population with diagnosed diabetes mellitus, the combined incidence of either sight impairment or severe sight impairment secondary to diabetic retinopathy was 1227, 1192 and 796 per million per year, respectively. For each year, the incidence of visual impairment was lower than the corresponding figure for 2005.
Following the introduction of a comprehensive retinal screening service, the incidence of visual impairment certification secondary to diabetic retinopathy in the Leeds Metropolitan area appears to be decreasing. However, a multifaceted approach, addressing all the avoidable risk factors, may be required to maintain this trend in view of the increasing prevalence of Type 2 diabetes.

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The atonal homolog 7 (ATOH7) gene encodes a transcription factor involved in determining the fate of retinal progenitor cells and is particularly required for optic nerve and ganglion cell development. Using a combination of autozygosity mapping and next generation sequencing, we have identified homozygous mutations in this gene, p.E49V and p.P18RfsX69, in two consanguineous families diagnosed with multiple ocular developmental defects, including severe vitreoretinal dysplasia, optic nerve hypoplasia, persistent fetal vasculature, microphthalmia, congenital cataracts, microcornea, corneal opacity and nystagmus. Most of these clinical features overlap with defects in the Norrin/β-catenin signalling pathway that is characterized by dysgenesis of the retinal and hyaloid vasculature. Our findings document Mendelian mutations within ATOH7 and imply a role for this molecule in the development of structures at the front as well as the back of the eye. This work also provides further insights into the function of ATOH7, especially its importance in retinal vascular development and hyaloid regression.